Cilostazol (general name of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl) has widely been used as thrombolytic drug, cerebral circulation improving drug, anti-phlogistic drug, anti-ulcer drug, hypotensive drug, drug for asthema, and phosphodiesterase inhibitor because it shows not only a high platelet aggregation supression action but also a phosphodiesterase inhibition action, an anti-ulcer action, a hypotensive action and an anti-phlogistic action. Cilostazol is usually used in the form of a tablet produced by adding excipients and other ingredients and compressing the mixture, and is orally administered. However, since the tablet is quickly disintegrated in the living body when orally administered, a large amount of cilostazol is released in the living body within a short time thereby to cause high concentration in blood, resulting in side effects such as headache, heavy feel in head, or pain. To prevent these side effects, a measure of administering a low-dose tablet in multiple dosing is suggested. However, it is ideal to produce a preparation capable of sustaining mild absorption for a long time by a single administration in order to avoid a complicated administration as much as possible. A fixed concentration of a drug in blood can be maintained by forming a slightly soluble drug into a sustained release preparation. However, since cilostazol is mainly absorbed at the upper portion of the digestive tract when administered orally and the absorption rate at the lower portion of the digestive tract is not sufficient, a single administration has its limits of the duration time of absorption. Accordingly, it becomes possible to maintain the concentration of cilostazol within desirable range in blood for a long time by improving absorption at the lower portion of the digestive tract.
Japanese Laid-open Patent Publication No. 7-291869 discloses that bioavailability of certain pharmaceutical agents is remarkably increased by forming a phosphonic acid diester derivative into a fine powder (average particle diameter of not more than about 10 μm).
However, when cilostazol was simply formed into a fine powder of less than about 10 μm in average particle diameter, its absorption rate at the lower portion of the digestive tract was very low.
U.S. Pat. No. 5,145,684 discloses particles consisting essentially of a crystalline drug substance having a surface modifier absorbed on the surface in amount sufficient to maintain an effective average particle size of less than about 400 nm wherein the bioavailability is increased.
But, this USP does not describe increasing the absorption rate at the lower portion of the digestive tract, of slightly soluble drug which exhibits an extremely low adsorption rate thereat.
WO 96/21448 discloses a resin particle having a particle size of not greater than 2,000 μm, which comprises an ethylene vinyl alcohol copolymer and 5 to 10% by weight of cilostazol incorporated therein. The resin particle, upon being administered orally, allows the concentration of cilostazol in blood to be kept constant over an extended period of time.
However, a production method of the resin particle is attended with many problems that an apparatus is on a large scale and an elevated temperature is required, and so on.
Japanese Laid-open Patent Publication No. 10-67657 discloses a multiple-unit type sustained release preparation, which contains two sustained release small tablets prepared by incorporating hydroxypropylmethylcellulose as a sustained release material into cilostazol. However, when a bulk cilostazol powder having an average particle diameter of about 20 μm is used, the resulting preparation showed a low absorbability at the lower portion of the digestive tube and the absorbability was not improved by adding a dispersing and/or solubilizing agent.